DESCRIPTION Age-related spatial memory decline occurs earlier in female mice relative to males. Although this sex difference coincides with the age- related cessation of regular estrous cycling (at 17 months of age), levels of ovarian hormones have been directly measure din the context of memory decline in aging. Therefore, it is unknown whether loss of these hormones contributes to sex differences in spatial memory decline. The proposed studies re designed to determine: 1) the age at which sex differences in spatial memory begin to emerge, 2) whether the onset of these six differences is related to age-related ovarian hormone decline, 3) whether neuroanatomical markers that are affected by age and ovarian hormones differentially decline in males and females, and 4) whether treatment of middle-aged females with hormone replacement will ameliorate their spatial memory deficit. In Experiment 1, designed to address questions 1-3, the spatial memory of male and female mice at 4 ages (5, 11, 14, and 17 months) will be measured in a 1-day water maze tasks, immediately after which the mice will be perfused and their brains removed for measurement of synapse and cholinergic neuron number. Blood will be collected for measurement of ovarian hormone levels. In Experiment 2, which will address question 4, ovariectomized 17 month-old female mice will be given hormone replacement and their spatial memory will be tested as in Experiment 1. The results of this study will provide insights into the mechanisms of, and possible treatments for, cognitive decline in menopausal women.